Autophagy appears to play a critical role in disposal of aggregation-prone proteins. For example, we have found that autophagy is responsible for disposal of insoluble polymers of mutant a1antitrypsin (AT) that cause liver disease in AT deficiency. In our recent work we have discovered that carbamazepine (CBZ), a drug that has been used for years as an anticonvulsant with a wide margin of safety, enhanced the autophagic disposal of mutant AT (ATZ) in cell line models of AT deficiency. Furthermore, in mouse models, CBZ markedly reduced the hepatic load of ATZ and reversed hepatic fibrosis, the tissue damage caused by ATZ. We have also recently developed a high-content screening (HCS) platform to identify therapeutic drugs that depends on a novel C.elegans model of AT deficiency. An initial screen of a low complexity drug library has identified 6 potential candidates, each of which markedly reduced intracellular accumulation of ATZ in the worm in a dose- and time-dependent manner. Interestingly, 4 of these candidates have been shown to enhance autophagic activity in general and to specifically enhance autophagic disposal of huntingtin, another aggregation-prone protein that causes human disease. Together, these data provide powerful validation of our HCS platform and of the autophagy enhancer strategy for at least 2 different types of aggregated proteins. So these results also provide a basis for testing autophagy enhancers on other diseases caused by aggregated proteins. Finally, a small pilot study shows that CBZ treatment reduces plaque load in the PS1/APP mouse model of Alzheimer's disease (AD). In this application we propose extensive testing of these autophagy enhancer drugs on neuropathologic and behavioral sequellae in the mouse AD model. The premise is that enhanced autophagy will prevent accumulation of neurotoxic intermediates in the brain. We will examine the effect of CBZ and its relative oxcarbazepine (OBZ) as well as candidates with autophagy enhancer activity that are identified in the C. elegans AT deficiency model/ HCS platform on Ab levels, plaque load, learning and memory in PS1/APP mice. These mice will be bred onto the GFP-LC3 background to permit easy monitoring of autophagy in the brain as an end-point measure of drug efficacy. We know that CBZ, OBZ and the other autophagy enhancer drugs identified so far are FDA-approved, have been used safely in humans and permeate the blood-brain barrier. The goal will be to position one or more of these drugs for clinical trials as soon as possible.